Obesity and Type 2 diabetes represent global health threats that predispose millions of individuals to reduced life expectancy and incur $117 billion in annual health care costs in the U.S. alone. Leptin acts via the long isoform of the leptin receptor (LepRb) to regulate energy balance, metabolism, and neuroendocrine function. It is crucial to understand the molecular basis of LepRb action in order to understand the mechanisms governing metabolic regulation. The long-term goals of our previous and proposed studies under this award, entitled, Molecular Mechanisms of Leptin Receptor/Jak2 Action, are to understand mechanisms of LepRb signaling and how these signals regulate neural function to control energy balance, glucose homeostasis, and endocrine function. Our findings have revealed two LepRb signals important for metabolic regulation: Tyr1138nSTAT3 and a second LepRb metabolic signaling pathway independent of LepRb tyrosine phosphorylation (the pY-independent pathway). To understand how LepRb controls metabolism and energy balance, we must determine how LepRb mediates the pY-independent second metabolic signal and understand how STATS and this pY-independent second signal modulate neuronal physiology to mediate downstream leptin action. Importantly, understanding how LepRb signals control physiology necessitates defining their long-term effects (as well as their acute actions). Our goals during this second period of MERIT funding are to resolve these issues. Since cultured cells do not permit the analysis of neural and physiologic leptin action, we will continue to generate and utilize LepRb mutant knock-in mouse lines, complemented by mouse models in which LepRb signaling molecules are disrupted in a cell- specific manner, with which to study the roles and mechanisms of action for defined LepRb signals in vivo. We propose to; Specific Aim 1: Identify the pY-independent LepRb moiety responsible for metabolic signaling in vivo. Specific Aim 2: Define the cell-autonomous roles for LepRb signals in the control of neuronal gene expression. Specific Aim 3: Determine the acute and chronic mechanisms by which LepRb signals modulate neural activity in vivo.